This is a revised application investigating immunoregulatory abnormalities in multiple sclerosis. MS is an inflammatory disease of the CNS which is postulated to be a Th1 type cell-mediated autoimmune disease. This laboratory has been investigating immune abnormalities in MS for a number of years and the current grant is presently in its 15th year. A great deal of progress has been made in understanding immune abnormalities in MS and in the past decade immune modulating therapies have been approved for MS and are becoming in more widespread use. Unanswered questions related to the immunology of MS include both basic questions of a precise definition of the nature of immune dysregulation that occurs in the disease and questions related to immune abnormalities and disease stage, and how immune abnormalities relate to current therapies. During the previous grant period, we established an important role for IL-12 in MS and defined changes in chemokine receptor expression in MS patients. Both of these appeared linked to disease stage and were consistent with the Th1 paradigm of the disease. We also found defective regulation of IFN-? production by IL-10. In the present competitive renewal we will: 1) analyze immune dysregulation in MS as measured by chemokine receptor expression both in the peripheral blood and the central nervous system; 2) investigate the role of IL-12 and IL-18 and dendritic cells in creating Th1 type immunologic milieu in MS; 3) Investigate immunoregulatory defects in MS related to regulation by IL-10 and TGF-a and to CD4+CD25+ regulatory cells; 4) determine the degree to which immune dysregulation and the abnormalities we have identified are linked to clinical disease activity and whether the dysregulation is altered by immunomodulatory therapies. The present application has been revised to include a more mechanistic approach to the questions being asked and incorporates the following new preliminary data: Th1 type chemokine receptor expression(CXCR6), new assays for myelin reactivity utilizing CFSE labeling, identification of abnormalities of dendritic cells in progressive MS and expression of PDL-1 in relapsing remitting MS, differential effects of IL-18 in progressive stages of disease, and identification of CD4+TGF-a+ T cells that have a regulatory phenotype that now can be investigated in MS. Our investigations will be greatly facilitated by our new Multiple Sclerosis Center with a large patient base and a dedicated MS MRI magnet and image analysis laboratory.